Immunological rejection is the leading cause of late failure of corneal grafts, most commonly in high-risk recipients with already vascularized corneas or with chronic inflammatory disease of the anterior segment. The endothelium is the principally affected tissue in at least half of clinical corneal allograft rejections. The expression of Class II alloantigens (HLA-DP, -DQ, -DR in humans; Ia in animals) may be induced by gamma interferon on a variety of target cells including corneal endothelium (Donnelly et al, Invest Ophth Vis Sci 26:575; Young et al., Invest Ophth Vis Sci 26:570; 1985). Immunogenic inflammation in the anterior segment of the eye is accompanied by the local production of Ia-inducing lymphokines,and the expression of Ia antigens on corneal endothelium (Donnelly and Prendergast, Cell Immunol 86:557, 1984; Donnelly et al., op. cit.). Class II alloantigen expression on a grafted cornea could increase the potential of the endothelium to excite local immune responses, and/or its susceptibility to lysis by immune effectors. In this event, the probability of success of high-risk clinical corneal grafts would be improved by matching for Class II alloantigens, or by inhibiting the induction of these antigens on the donor cornea. The present studies will define in detail the time course of local Ia-inducing lymphokine production and endothelial Ia expression during the rejection of orthotopic corneal allografts in a rabbit model. The ability of Ia-bearing endothelial cells to initiate the afferent limb of the immune response by inducing helper T lymphocyte proliferation, inducing the formation of allospecific cytolytic T lymphocytes (CTL), and processing and presenting alloantigens to helper T cells and CTL, will be determined in an inbred mouse in vitro model. The susceptibility of Ia-bearing corneal endothelium to lysis by CTL, representing the efferent limb of the immune response, also will be determined in an in vitro mouse model. The findings in animal models will be correlated with human corneal allograft rejection by immunohistochemical staining of DR and DP/DQ antigens in rejected corneas and in corneas from chronically inflamed eyes.